Abstract (30 lines): There is currently no imaging modality for the early diagnosis of rheumatoid arthritis (RA) that can provide specific molecular information in a safe, inexpensive, and completely non-invasive manner. Damage from RA is generally considered irreversible, but effective therapies exist. Therefore, there is a critical need to develop an accurate, inexpensive, safe, and sensitive imaging method for early stage diagnosis of RA and monitoring treatment response to improve clinical decision making. The long-term goal is to develop a patient-friendly (compliant) and reliable method for the early detection and treatment monitoring of RA to reduce the burden of disease (both cost and morbidity). The overall objective of this proposal, which is the next step to achieving this goal, is to identify near-infrared fluorescent imaging agents that have sufficient absorption, distribution, and targeting in animal models to provide the needed molecular specificity for the early detection of RA at clinically relevant depths when given orally or by subcutaneous injection. The central hypothesis of the proposal is that targeted near-infrared optical imaging probes following oral (PO) or subcutaneous injection (SC) will be able to reach sufficient target-to-background concentrations in rodents for early diagnosis and treatment monitoring applications. The rationale behind this approach is to identify targeted optical probes that can be self- administered by patients (through a pill or injector pen) and rapidly imaged in an office setting on current FDA approved imaging devices for early diagnosis of RA and monitoring treatment response. Our hypothesis will be objectively tested through the following two specific aims. Aim 1: Identify optical molecular imaging probes for detection of RA following oral or subcutaneous delivery in animal models. Based on our computational simulations, our working hypothesis is that integrin, folate, and somatostatin receptor targeted probes can achieve sufficient uptake after oral or SC administration for early diagnosis when scaled to clinically relevant depths. Aim 2: Quantify the change in target expression and image intensity of oral and subcutaneously delivered probes after treatment with disease modifying drugs to monitor treatment response in mice and rats. Our working hypothesis is that disease-modifying anti-rheumatic drugs (DMARDs) will change integrin expression and imaging signal back to the level of healthy controls following complete remission in animal models treated with DMARDs versus controls. Self-administered imaging agents will enable early, potentially subclinical, detection of RA by providing physicians with both spatial and molecular information in a rapid and inexpensive manner in a format less invasive than a blood test. The method could also be used for treatment monitoring in patients to shorten the follow up time on evaluating response from 1-3 months to weeks. This represents a paradigm shift in early detection by combining biophysical simulations of near-infrared light distribution, oral or SC bioavailability of small molecules, and molecular imaging agent pharmacokinetics to develop safe, cost-effective, and reliable self-administered molecular imaging probes for RA.